Cerebral cavernous malformations (CCMs) are the most common brain vascular malformations and are detected in the population at a rate of approximately 0.6 per 100,000. Recognized as familial or sporadic cases, CCMs are characterized as single of multi cluster of enlarged capillary-like channels with a single layer of endothelium and without intervening brain parenchyma. There are specific alterations in brain endothelial barrier components that ultimately lead to vascular hyperpermeability, extravasation of red cells and inflammatory response in brain parenchyma. Patients with CCMs may present with seizures, focal deficits, or nonspecific headaches and as most common complication is hemorrhagic stroke. Although significant effort has been made in defining the genes mutations involved in inherited CCMs, the intra- and intercellular pathogenic mechanisms responsible for vascular hyperpermeability are still largely unknown. The proposed study is designed to elucidate critical molecular events in maintaining the integrity of the brain endothelial barrier and how these are altered cerebral cavernous malformation type 3. In particular, the proposal will address the multisequential events involved in organization of the TJ complex. It will highlight how the interaction between signaling molecules, CCM3 protein and an actin cytoskeleton protein, cortactin, affect the organization and stability of brain endothelial tight junctional complex. Specifically, the following objectives will be evaluated: a) the functional and morphological consequence of CCM3 absence on TJ complex/actin cytoskeleton interactions in conditions of CCM3 pathology and b) the role of CCM3-cortactin interaction in establishing stable interactions between ZO-1 and the actin cytoskeleton and ZO-1 and claudin-5. Collectively, these studies will provide new information related to the mechanisms involved in maintaining the brain endothelial barrier that is relevant not only to CCM3 but also to multiple disease states. Hopefully, this will help to elucidate novel therapeutic strategies to restore vascular hyperpermeability. PUBLIC HEALTH RELEVANCE: Normally, the brain is protected from changes in the bloodstream by the blood-brain barrier situated at the brain blood vessels. Defects in that barrier may be important for developing stroke, epilepsy and other neurological diseases. One disease that affects the blood-brain barrier is cerebral cavernous malformation-3. This vascular malformation is characterized by thin-walled vascular cavities that may rupture. The purpose of this study is to highlight the molecular mechanisms underlying vessel hyperpermeability in this condition. This may provide a foundation for developing novel therapeutic strategies to lessen the impact of this disease as well as other neurological conditions that affect the blood-brain barrier.